Genetic and epigenetic profiling of BRCA1/2 in ovarian tumors reveals additive diagnostic yield and evidence of a genomic BRCA1/2 DNA methylation signature.

Poly-ADP-ribose-polymerase inhibitor (PARPi) treatment is indicated for advanced-stage ovarian tumors with BRCA1/2 deficiency. The "BRCAness" status is thought to be attributed to a tumor phenotype associated with a specific epigenomic DNA methylation profile. Here, we examined the diagnostic impact of combined BRCA1/2 sequence, copy number, and promoter DNA methylation analysis, and evaluated whether genomic DNA methylation patterns can predict the BRCAness in ovarian tumors.

Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders.

Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results.

Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions.

Conventional genetic testing of individuals with neurodevelopmental presentations and congenital anomalies (ND/CAs), i.e., the analysis of sequence and copy number variants, leaves a substantial proportion of them unexplained.

BAFopathies' DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin-Siris and Nicolaides-Baraitser syndromes.

Coffin-Siris and Nicolaides-Baraitser syndromes (CSS and NCBRS) are Mendelian disorders caused by mutations in subunits of the BAF chromatin remodeling complex. We report overlapping peripheral blood DNA methylation epi-signatures in individuals with various subtypes of CSS (ARID1B, SMARCB1, and SMARCA4) and NCBRS (SMARCA2). We demonstrate that the degree of similarity in the epi-signatures of some CSS subtypes and NCBRS can be greater than that within CSS, indicating a link in the functional basis of the two syndromes.

Clinical Validation of Copy Number Variant Detection from Targeted Next-Generation Sequencing Panels.

Next-generation sequencing (NGS) technology has rapidly replaced Sanger sequencing in the assessment of sequence variations in clinical genetics laboratories. One major limitation of current NGS approaches is the ability to detect copy number variations (CNVs) approximately >50 bp. Because these represent a major mutational burden in many genetic disorders, parallel CNV assessment using alternate supplemental methods, along with the NGS analysis, is normally required, resulting in increased labor, costs, and turnaround times.

Identification of epigenetic signature associated with alpha thalassemia/mental retardation X-linked syndrome.

Background: Alpha thalassemia/mental retardation X-linked syndrome (ATR-X) is caused by a mutation at the chromatin regulator gene . The mechanisms involved in the ATR-X pathology are not completely understood, but may involve epigenetic modifications. ATRX has been linked to the regulation of histone H3 and DNA methylation, while mutations in the gene may lead to the downstream epigenetic and transcriptional effects.

The defining DNA methylation signature of Floating-Harbor Syndrome.

Floating-Harbor syndrome (FHS) is an autosomal dominant genetic condition characterized by short stature, delayed osseous maturation, expressive language impairment, and unique facial dysmorphology. We previously identified mutations in the chromatin remodeling protein SRCAP (SNF2-related CBP Activator Protein) as the cause of FHS. SRCAP has multiple roles in chromatin and transcriptional regulation; however, specific epigenetic consequences of SRCAP mutations remain to be described.

Clinical Validation of Fragile X Syndrome Screening by DNA Methylation Array.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. It is most frequently caused by an abnormal expansion of the CGG trinucleotide repeat (>200 repeats) located in the promoter of the fragile X mental retardation gene (FMR1), resulting in promoter DNA hypermethylation and gene silencing. Current clinical tests for FXS are technically challenging and labor intensive, and may involve use of hazardous chemicals or radioisotopes.

DNA methylation analysis in constitutional disorders: Clinical implications of the epigenome.

Genomic, chromosomal, and gene-specific changes in the DNA sequence underpin both phenotypic variations in populations as well as disease associations, and the application of genomic technologies for the identification of constitutional (inherited) or somatic (acquired) alterations in DNA sequence forms a cornerstone of clinical and molecular genetics. In addition to the disruption of primary DNA sequence, the modulation of DNA function by epigenetic phenomena, in particular by DNA methylation, has long been known to play a role in the regulation of gene expression and consequent pathogenesis. However, these epigenetic factors have been identified only in a handful of pediatric conditions, including imprinting disorders.

Chemotherapy-induced amenorrhea in patients with breast cancer with a BRCA1 or BRCA2 mutation.

Purpose: To determine the likelihood of long-term amenorrhea after treatment with chemotherapy in women with breast cancer who carry a BRCA1 or BRCA2 mutation.

Patients And Methods: We conducted a multicenter survey of 1,954 young women with a BRCA1 or BRCA2 mutation who were treated for breast cancer. We included premenopausal women who were diagnosed with invasive breast cancer between 26 and 47 years of age.

The impact of population-based screening studies on hemochromatosis screening practices.

Objectives: To determine if community population screening studies for hemochromatosis affected HFE genetic screening practices in non-study populations.

Methods: An audit of all genetic testing for HFE mutations at London Health Sciences Center, London, Ontario, Canada from 1997 to 2010 was performed. The frequency of genetic testing and the frequency of C282Y homozygous cases identified during the years of the London Red Cross (1998-1999) and HEIRS (2000-2005) screening studies were compared with the corresponding frequencies in the specified years outside this range (1997-1998 and 2006-2010).

Novel 95G>A (R32K) somatic mosaic connexin 32 mutation.

Charcot-Marie-Tooth disease (CMT) is among the most common inherited disorders of the peripheral nervous system, and it is broadly categorized as demyelinating type 1 or axonal type 2 based on nerve conduction studies. Mutations in discrete genes usually segregate into a single phenotype. However, mutations in connexin 32 (Cx32) can produce both axonal and demyelinating CMT phenotypes.

Infertility, treatment of infertility, and the risk of breast cancer among women with BRCA1 and BRCA2 mutations: a case-control study.

Background: Women with a breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2) mutation are at increased risk for developing breast and ovarian cancer. Various reproductive and hormonal factors have been shown to modify the risk of breast cancer. These studies suggest that estrogen exposure and deprivation are important in the etiology of hereditary cancer.

A model for GFR alpha 4 function and a potential modifying role in multiple endocrine neoplasia 2.

Mutations of the RET proto-oncogene are found in the majority of patients with the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). A minority of cases, however, have no detectable RET mutation and there is considerable phenotypic variation within and among MEN 2 families with the same RET mutation, suggesting a role for other loci in this disease. A candidate for such a gene is glial cell line-derived neurotrophic factor receptor alpha 4 (GFRA4), which encodes a cell surface-bound co-receptor (GFR alpha 4) required for interaction of RET with its ligand persephin.

Genotype/Phenotype Correlations in X-Linked Dominant Charcot-Marie-Tooth Disease.

We have studied the relationship between genotype, clinical phenotype, and pathology in 13 families with dominant X-linked Charcot-Marie-Tooth (CMT) neuropathy. Connexin32 (Cx32) gene mutations were spread throughout the coding region and included eight missense mutations, one 8-bp deletion/4-bp insertion frame shifting mutation, two nonsense mutations, and one deletion of the entire coding sequence. One hundred sixteen affected CMTX patients (53 males and 63 females) and 63 unaffected, at-risk individuals were compared by neurological and electrophysiological examinations and analyzed by gender; nerve biopsies were available from seven index cases.